1. Field of the Invention
The invention is directed to a process for preparing an aryl 8-aza-bicyclo[3.2.1]octane compound which is useful as an intermediate for the preparation of medicinal agents. In particular, the invention is directed to the preparation of intermediates to mu opioid receptor antagonist agents.
2. State of the Art
Compounds that demonstrate antagonism at mu opioid receptors are expected to be useful for treating or ameliorating medical conditions mediated by mu opioid receptor activity, such as disorders of reduced motility of the gastrointestinal tract. For example, such compounds are expected to be useful for the treatment of opioid-induced bowel dysfunction or post-operative ileus. U.S. application Ser. No. 11/711,961 has recently disclosed a series of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-(substituted)phenyl compounds, that have exhibited activity as mu opioid receptor antagonists. Of particular interest within this series are compounds of formula (I):
wherein, for example, R2 is cyclohexyl or 4,4-difluorocyclohexyl, and R4 is C1-4alkyl substituted with one or two hydroxyl substituents. As disclosed in the cited application, preparation of such compounds relies on a key intermediate, the compound 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide:
having the endo orientation of the benzamide moiety with respect to the 8-aza-bicylo[3.2.1]octyl group of the final product.
In order to make use of the above class of mu opioid receptor antagonists as medicinal agents, it would be desirable to have an efficient process for preparing 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide with high stereospecificity. Since the efficiency of the synthesis of organic compounds decreases dramatically with the number of process steps, it would be desirable for the synthetic process to require a minimum number of process steps.